Targeting adenosine A_2A receptor antagonism for treatment of cancer

ABSTRACT

Introduction: Adenosine A_2A Receptor (A_2AR) antagonists are an emerging class of agents that treat cancers, both as a monotherapy and in combination with other therapeutic agents. Several studies support the accumulation of extracellular adenosine in the tumor microenvironment as a critical mechanism in immune evasion implicating A_2AR antagonists for use in immuno-oncology.

Areas covered: In this perspective article, the authors briefly outline the history of the A_2AR antagonist field for central nervous system indications and give their perspective on the status of agents progressing today in oncology. A brief description of the biological rationale in oncology is given. A particular focus of this article is progress in A_2AR structure determination and its impact on Structure-Based Drug Design.

Expert opinion: Our understanding of the A_2AR antagonist mechanism of action has changed and is now being clinically validated by several key companies in the oncology field. This area is likely to rapidly develop over the next 1–2 years.

KEYWORDS:

• G protein-coupled receptor
• GPCR
• adenosine receptors
• A_2AR
• structure-based drug design
• SBDD
• immune-oncology

Article highlights

• Adenosine A_2A Receptor (A_2AR) antagonists have been developed over many years for the potential treatment of central nervous system (CNS) disorders such as Parkinson’s disease

• The hypothesis that extracellular adenosine in the tumor microenvironment is a critical mechanism in immune evasion has generated significant interest in the use of A_2AR antagonists in cancer

• A_2AR was one of the first G Protein-Coupled Receptors (GPCRs) to yield protein-ligand X-ray structures facilitating the use of Structure-Based Drug Design (SBDD) for the discovery of novel agents

• A_2AR has been extensively studied using biophysical techniques, and multiple X-ray structures have now been solved with both antagonist and agonist ligands

• A_2AR antagonists are now being studied clinically in immune oncology in what has become a competitive and rapidly developing field.

Acknowledgments

The authors thank Benjamin Tehan for preparation of Figure 1 and Richard Woessner, Kris Sachsensmeier and Deanna Mele for helpful discussions.

Declaration of interest

M Congreve is the Senior Vice President of Drug Discovery at Heptares Therapeutics while GA Brown is the Head of Medicinal Chemistry at Heptares Therapeutics Ltd. A Borodovsky and ML Lamb are meanwhile employees of AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.